In this section, we discuss several aspects of related work, including background and conventional technologies.
Burns are among the most painful and debilitating battlefield wounds faced by the US warfighter. Burn wounds turn deadly when infection sets in. Since military operations began in Iraq in March 2003, hundreds of US military personnel have sustained burn injuries from explosions and other implements of war such as IED's [E. M. Renz et al. Long Range Transport of War-Related Burn Casualties, J Trauma. 64, S136-S145 (2008)], Acute burn injury pain is a source of immense suffering, and it has been linked to debilitating chronic pain and stress-related disorders. Severe pain is felt during acute treatment and rehabilitation, especially during dressing changes, debridement's, and skin grafting, and continues through long-term follow-up. The backbone of burn analgesia is opioid therapy, typically administered via oral or parenteral routes. The systemic use of opioid medications in burn patients is complicated by the side effects such as tolerance, hyperalgesia, hemodynamic instability, respiratory depression, and dependence. Therefore, besides the systemic administration of analgesics, attempts have been made to control the pain locally using topical analgesics which have shown encouraging results [T. Long, T. Cathers, R. Twillman, T. O'Donnell, N. Garrigues, T. Jones, Morphine-Infused Silver Sulfadiazine Cream for Burn Analgesia: A Pilot Study, Journal of Burn Care & Rehabilitation, 22, 118-123, (2001)]. Such topical dressings can be used to protect the burn wound from infection and thereby aid in wound healing if antimicrobial properties can be imparted to them. Topical antimicrobial-analgesic dressings can also be used to treat major irritation/pain problems such as abrasions, friction irritations and pressure sores (blisters).
Fentanyl, an opioid analgesic was incorporated into an antimicrobial wound dressing based on silver containing clay mats. This fentanyl-loaded silver containing clay mat can provide controlled delivery of analgesic drugs to wounds while assisting in wound healing with its antimicrobial properties. Silver containing clay mats were prepared and evaluated in vitro for their antimicrobial activity and their ability to provide controlled release of fentanyl. The antimicrobial properties of both silver containing claymats without Fentanyl and with Fentanyl loading were demonstrated using Kirby-Bauer assay tests. After optimizing the kinetics of the opioid delivery in vitro, the efficacy of silver containing claymats with fentanyl as a topical analgesic dressing was tested using a standard hot plate animal model. The Hot Plate test, in a rodent model, clearly demonstrated the ability of silver containing claymats with fentanyl patches to elicit cutaneous antinociception activity due to regional delivery of subtherapeutic doses of fentanyl. Pain and Infection are the two major complications associated with second-degree burn injuries. Silver containing claymats with fentanyl mat is a single patch device that can be used to alleviate pain and prevent infection in burn injuries.
Burn Injury Pain and Action of Analgesics
The description of the pain pathway as provided by Kehlet et al. [H. Kehlet J. B. Dahl, The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth. Analg; 77,1049 (1993)] and Gottschalk et al. [H. Kehlet, J. B. Dahl, The value of “multimodal” or “balanced analgesia” in postoperative pain treatment, Anesth Analg; 77,1049 (1993)] is as follows: “Both the peripheral and the central nervous systems (CNS) are involved in the perception of pain. The transmission of burn wound pain stimuli begins with peripheral nociceptors. The pain message from the nociceptors is transmitted via A-delta and C fibers to the dorsal horn of the spinal cord [P. Richardson, L. Mustard, The management of pains in the burns unit, Burns, 35, 921-936, (2009)]. The sensitivity of nociceptors is further enhanced by many tissue factors and inflammatory chemicals released in the course of tissue injury.” Therefore, the baseline pain management must include treatment of both nociceptive and neuropathic components. Nociceptive receptors can be controlled by local medication while neuropathic parts will require systemic administration of analgesics.
Action of Topical Analgesics
Treatment for reducing pain involves the use of common and opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and adjuvant analgesics [M. P. Flores, A. P. Rocha de Castro, J. S. Nascimento, Topical Analgesics, Revista Brasileira de Annesesiologie, 62, 244-252, (2012)]. Pharmacologically, it is known that the main mechanism of analgesics is to act at specific sites located in the CNS and periphery. This observation led the topical administration of pain reliever drags such as NSAID's, local anesthetics, capsaicin, tricyclic antidepressants, ketamine, clonidine, opioids, and cannabinoids. For example, fentanyl transdermal patches are used to treat chronic pain from cancer or in the post-operative setting [M. Lane, The transdermal delivery of fentanyl, European Journal of Pharmaceutics and Biopharmaceutics, 84, 449-455, (2013)]. The topical application of these dregs allows high concentrations in peripheral effector sites. Thus, undesirable side effects are less likely to occur compared to delivering these drugs systemically.
Human skin consists of three main layers: the epidermis, dermis, and hypodermis. An applied drug most traverse these structural layers, encountering several lipophilic and hydrophilic domains on the way to the dermis where absorption into systemic circulation is rapid due to large capillary beds [L. Margetts, R. Sawyer, Transdermal Drug Delivery: Principles and Opioid Therapy, Continuing Education in Anesthesia, Critical Care & Pain, 7, 171-176, (2007)]. Therefore, the action of transdermal supply of analgesic will take more time than systemic administration of the same drug. For example, after initial application, fentanyl concentrations in blood increase gradually, generally leveling off between 12 and 24 h. In the case of a burn injury, the drug absorption rate through the skin will also be affected by various other factors such as the degree of burn, thickness of skin and body temperature. The conventional wisdom is that even though opioid drugs are applied locally on the skin, the main analgesic action of opioids occurs only in the spinal cord. This will require the drug to be absorbed into the blood and travel from the skin surface to the spinal cord. The treatment of severe pain with opioids has thus far been limited by their unwanted central side effects.
Recent pioneering work by Stein et al. and others promises the possibility of opioid analgesic action outside the CNS. Recently, opioid receptors have been identified on peripheral processes of sensory neurons. Opioids can attenuate the excitability of peripheral nociceptor terminals, reduce the conduction of pain signals and the release of excitatory proinflammatory neuropeptides (substance P, calcitonin gene-related peptide) from peripheral sensory nerve endings. In other words, areas with injury or burns generate chemical substances that irritate nerve endings even more and cause pain. Opioids apparently decrease the formation of these substances and decrease the response of nerve fibers to these substances. The modulating effect of fentanyl on the nerve endings can be translated into a clinically significant effect on pain relief.
Clays as a Drug Delivery Medium
Fentanyl loaded silver containing claymat patches were prepared using montmorillonite clay as the matrix for Fentanyl. Clays are common ingredients in pharmaceutical products. Clay minerals are naturally occurring inorganic cationic exchangers that can undergo ion exchange with basic drugs in solution. In addition to ion-exchange, organic molecules can bond to clays via physical adsorption and ion-dipole interactions of acidic and non-ionized molecules. For example, Wai and Banker demonstrated the loading of alkaloids in montmorillonite clay [K. N. Wai, G. S. Banker, Some physicochemical properties of the montmorillonites. J. Pharm. Sci. 55, 1215-1220 (1966)]. One major advantage of using clays to deliver drugs compared to other delivery systems is the very low risk of ‘dose dumping’. Common topical medical dressings such as gauze, membranes and textiles can be subjected to dose dumping easily due to external forces. Thus, a material of high chemical and mechanical resistance is required to develop a safe, high potency opioid transdermal drug delivery vehicle [C. Aguzzi, P. Cerezo, C. Viseras, C. Caramella, Use of clays as drug delivery systems: Possibilities and limitations, Applied Clay Science, 36, 22-36, (2007)]. Clays are the most optimum storage and delivery systems for analgesics because of their mechanical and chemical stability. Fentanyl has been loaded into a metakaolin clay, which provided a mechanically strong sustained drug release medium [K. N. Wai, G. S. Banker, Some physicochemical properties of the montmorillonites. J. Pharm. Sci. 55, 1215-1220 (1966)]. The multifunctional patch can be used in skin graft patients, for pain management at the skin donor site.
The transdermal absorption of opioid drugs like fentanyl may take up to 8-12 h to take action. However, the injured patient requires the drugs to provide immediate relief. One approach is to use local anesthetics such as Lidocaine base or Loperamide base instead of Fentanyl or in combination with Fentanyl.
Lidocaine hydrochloride molecules strongly bound to the claymat through an intercalation process. For example, Kevadiya et al. intercalated Lidocaine hydrochloride into montmorillonite clay by ion exchange and investigated the controlled drug release [B. D. Kevadiya, G. V. Joshi, H. M. Mody, H. C. Bajaj, Biopolymer-clay hydrogel composites as drug carrier: Host-guest intercalation and in vitro release study of lidocaine hydrochloride, Applied Clay Science, 52, 364-367 (2011)]. The in vitro release experiments showed that lidocaine release from montmorillonite clay was controlled by pH of the extracting liquid medium. Lidocaine was released faster at alkaline or neutral pH. Abdel-Mohsen et al. studied the ionic state of lidocaine as a function of pH [M. G. Abdel-Mohsen, H. A. Mohamed, H. M. A. Wadood, Study of the effect of montmorillonite and Florite on the dissociation constant, release and local anesthetic activity of lidocaine, STP Pharma Sciences, 4, 295-300 (2001)]. They also demonstrated that Lidocaine hydrochloride release in water is affected by the pH indicating the interaction of lidocaine cations with the clay surface. Conditions for transdermal drug delivery is different from in vivo drug delivery or in vivo drug release. The transdermal delivery of drugs occurs in a dry state without a major amount of fluids. In comparison, drug delivery through oral administration occur in the presence of a large amount of bodily fluids and strongly depends on the pH of the medium.
The availability of fluids on the skin surface to extract the drug from the drug delivery transdermal patches is very small or even absent on dry skins. Therefore, the transdermal mat should allow free mobility of the drug through the patch. This flow will be restricted if the polymers are used in the preparation of claymats.
The ammonium (+NH— and +N(C2H5)2—) groups on lidocaine hydrochloride interact strongly with the clay surface. No leaching of lidocaine hydrochloride was from the mats observed due to the strong binding of lidocaine hydrochloride with the claymat and silver containing claymat samples. Therefore, it was decided to use lidocaine base instead of lidocaine hydrochloride. This resulted in an increase in the release of lidocaine base from the claymat and silver containing claymat samples during the drug release testing.